Trifluoroacetic acid → HCID 2761849, compound

means resin polymer.) (1) A mixture of N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline ethyl ester (3.00 g), LiOH (10 mmol), THF (25 mL), MeOH (10 mL) and H2O (5 mL) was stirred at room temperature overnight. The mixture was then heated at 74° C. overnight. The mixture was concentrated in vacuo, and water was added. The mixture was washed with Et2O and the aqueous layer was made acidic with the addition of 1N H2SO4. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, and evaporated to give N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (3.02 g). MS (m/z) 284 (MH+-t-Boc); mp: 143.9° C. (2) To a solution of the compound obtained above (2.45 g) in DMF (100 mL) was added Merrifield Resin (4.70 g) and KF (1.1 g). The resulting mixture was stirred under N2 at 80° C. overnight. The resin was filtered, and washed thoroughly with MeOH, H2O and CH2Cl2, then dried in vacuo overnight to yield the resin-bound N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (6.66 g); FTIR (cm−1) 1740, 1697, 1397, 1131, 1011. (3) The compound obtained above was then deprotected using a 50% solution of TFA in CH2Cl2, followed by thorough washing, to give the resin-bound 2-(4-bromobenzyl)proline (6.09 g); FTIR (cm−1) 1722. (4) To the compound obtained above (200 mg) was added a DMF solution of 2,6-dichloro-4-pyridyl isocyanate (5 equiv.). This mixture was shaken at room temperature in a sealed receptacle overnight. The mixture was filtered, and the resin was washed with DMF, water and MeOH, and air-dried to give the resin-bound N-[(2,6-dichloro-4-pyridyl)carbamoyl]-2-(4-bromobenzyl)proline. (5) A solution of DIEA (350 μL) in DMF (5 mL) was added to the compound obtained above, and the resulting mixture was then shaken at 50° C. for 2 hours, then at room temperature overnight. The resin was filtered and washed with MeOH, and the filtrate was evaporated. The residue was purified by reverse phase HPLC (gradient of 0%-70% CH3CN in water) to yield 3-(2,6-dichloro-4-pyridyl)-5-(4-bromobenzyl)-1,3-diazabichclo[3.3.0]octane-2,4-dione (58.0 mg). MS (m/z): 456 (MH+); mp: 76.3° C.;

ORD record

ord-28c7e07324354dac9701e843585dda89

Source dataset

uspto-grants-2008_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07342012B2